1. Field of the Invention
The present invention is directed to the use of compounds possessing both angiotensin converting enzyme and neutral endopeptidase inhibitory activity (and classified in the art as vasopeptidase inhibitors) for the treatment of nephropathy in diabetic or non-diabetic patients, including diabetic and non-diabetic nephropathy, glomerulonephritis, glomerular sclerosis, nephrotic syndome, hypertensive nephrosclerosis, microalbuminuria or end stage renal disease, or to a method of treatment and/or prophylaxis of insulin resistance or of metabolic diseases associated with advanced glycation end-products, diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, myocardial infarction and/or diabetic cardiomyopathy, or to a method of treatment and/or prophylaxis of atherosclerosis or endothelial dysfunction.
2. Description of the Art
Angiotensin-Converting Enzyme (ACE) is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor which also stimulates aldosterone secretion by the adrenal cortex. ACE inhibition prevents both the conversion of angiotensin I to angiotensin II and the metabolism of bradykinin, resulting in decreased circulating angiotensin II, aldosterone and increased circulating bradykinin concentrations. In addition to these neurohormonal changes, decreases in peripheral resistance and blood pressure are observed, particularly in individuals with high circulating renin. Other pharmacological effects associated with ACE inhibition include regression of left ventricular hypertrophy, improvement in the clinical signs of heart failure, and reduction in mortality in patients with congestive heart failure (CHF) or left ventricular dysfunction after myocardial infarction.
Neutral endopeptidase (NEP) is an enzyme responsible for the metabolism of atrial natriuretic peptide (ANP). Inhibition of NEP results in increased ANP concentrations, which in turn leads to natriuresis, diuresis and decreases in intravascular volume, venous return and blood pressure. ANP is released by atrial myocytes in response to atrial stretch or increased intravascular volume. Elevated plasma concentrations of ANP have been demonstrated as a potential compensatory mechanism in various disease states, including congestive heart failure, renal failure, essential hypertension and cirrhosis.
The secretion of ANP by atrial myocytes causes vasodilation, diuresis, natriuresis, and the inhibition of renin release and aldosterone secretion. In contrast, angiotensin II results in vasoconstriction, sodium and water reabsorption, and aldosterone production. These two hormonal systems interact in a reciprocal or counterbalancing manner to maintain normal physiologic vascular and hemodynamic responses.
U.S. Pat. No. 5,430,145, European patent EP 481522 and WO patent application PCT/EP 02/03668 disclose tricyclic mercaptoacetylamide derivatives of formula (I) useful as ACE and NEP inhibitors, i.e. for the treatment and/or prevention of heart failure and hypertension. Compounds that inhibit both angiotensin-converting enzyme and neutral endopeptidase are classified as “vasopeptidase inhibitors” (VPIs), and act to both reduce the activity of the renin-angiotensin system and to potentiate the vasodilatory, natriuretic and antiproliferative effects of bradykinin and natriuretic peptides. In preclinical studies, VPIs display a broad profile being effective in all tested models of hypertension and heart failure, and ongoing clinical studies suggest that VPIs possess advantages over other therapies (Jean Bralet and Jean-Charles Schwartz, TRENDS in Pharmacological Sciences, 22 (3), 106-109 (2001)).